No abstract

A series of novel ¡-peptide ribonucleic acid (¡PRNA) oligomers, possessing alternative ¡PRNAGly/Lys sequences, were newly designed, synthesized, and evaluated as the secondgeneration PRNA. As expected, the ¡PRNA with Lys formed stable sequence-specific complex with the complementary DNA, for which both the hydrogen-bonding interactions between the complementary nucleobase pairs and the electrostatic interactions between the ammonium cation on the lysine side chain and the DNA phosphate anion on the backbone are jointly responsible.Recently gene therapeutic methods for selectively down regulating the expression of the genetic information of cancer growth and disease related proteins by specific recognition and binding to the target mRNA through the siRNA and antisense RNA strategies have become a target of intensive studies.1 In particular the down regulation of genetic information by siRNA is considered one of the most powerful tools not only for molecular biology and genetic engineering but also for oligonucleotide therapeutics.1 Nevertheless, the currently used siRNA molecules have some drawbacks, such as poor reproducibility, resulting probably from intracellular instability, low cell membrane permeability, and low binding affinity.1 Most of the other gene therapeutic methods share some of these problems, and hence these are regarded as the most crucial research targets to be attacked.2 To remedy these drawbacks, a variety of modified nucleotides and nucleic acid model compounds have been proposed for a better resistance to nucleases and an enhanced hybridization affinity of the oligomer. Peptide nucleic acid (PNA) with a peptide-based backbone structure is one of the most successful nucleic acid models. 3Inspired by the unique backbone structure and properties of PNA, several attempts to improve and/or functionalize existing gene therapeutic compounds have been done through the modification of the oligonucleotide backbone 2 as well as the development of nucleic acid model compounds with different backbone structures.2 However, these hitherto reported nucleic acid derivatives and their model compounds have an intrinsic restriction or disadvantage, lacking the ability to actively control the function of oligonucleotide therapeutics by internal physiological and/or external physical/chemical stimuli.We have recently proposed a new category of nucleic acid model compound; named peptide ribonucleic acid (PRNA), in which a 5¤-amino-5¤-deoxypyrimidine ribonucleoside (1) moiety is appended to an oligo(£-L-glutamine) backbone through the ribose 5¤-amino group (Chart 1).4 £PRNAs form stable complexes with complementary DNAs (cDNAs) and RNAs with high nucleobase sequence specificities. Furthermore, the recognition and complexation behavior of £PRNAs with target RNAs can be controlled by borax added as an external factor through the anti-to-syn switching of the nucleobase orientation, which is attributable to the synergetic effect of the borate ester formation with the 2¤,3¤-cis diol of the ribose moiety and the intramo...

In this study, a series of novel alpha-Peptide ribonucleic acid (alpha-PRNA) oligomers, possessing alternative alpha-PRNA/arginine or serine sequences, were newly designed, synthesized, and evaluated as the third-generation PRNA. As expected, these alpha-PRNAs formed highly stable sequence-specific complexes with the complementary RNAs, for which both the conventional hydrogen-bonding interactions between the complementary nucleobase pairs and the electrostatic interactions between the arginine's guanidinium cation and the RNA's phosphate anion on the backbone are jointly responsible. Moreover, in the cases of alpha-PRNA and single point mismatched DNA mixing systems, appreciable T(m) could not be observed, thus alpha-PRNAs containing Arg were expected to have high nucleobase sequence discrimination abilities. It was demonstrated that the recognition behavior of alpha-PRNA with Arg/Ser backbone with complementary RNA can be controlled externally through the orientation change of pyrimidine nucleobase induced by borate ester formation of the ribose's 2',3'-cis-diol.

A novel nucleic acid model using alpha-peptide ribonucleic acid (alpha-PRNA) possessing alternative alpha-PRNA/lysine and alpha-PRNA/arginine sequences, where the lysine or arginine residue are expected to stabilize the complex not only by the conventional hydrogen-bonding interactions between the complementary nucleobase pairs but also through the electrostatic interactions between basic amino acid side-chain groups and DNA's phosphate anions on the backbone. These alpha-PRNAs form stable sequence-specific complex with the complementary DNA.

Recently, we have demonstrated that effective control of the recognition behavior of peptide ribonucleic acid (PRNA) with complementary DNA is possible through the anti-to-synorientational change of pyrimidine nucleobase induced by borate ester formation. In this study, DNA-PRNA chimera was prepared by the solidphase synthesis. In the DNA-PRNA chimeras, both PRNA and DNA domains work as recognition sites for the complementary DNA/RNAs to form stable complex, while DNA-RNA hybrids formed in the DNA domains of DNA-PRNA chimera should be substrates to the hydrolysis by RNase H and PRNA moieties work as recognition control/switching devices and as inhibitor for the hydrolysis by exonucleases. Interaction of the DNA-PRNA chimera with DNA and RNA has been discussed.